Pyruvate Dehydrogenase Complex Deficiency: Updating the Clinical, Metabolic and Mutational Landscapes in a Cohort of Portuguese Patients

Background: The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. Results: The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1α subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying what seems to be a private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas the lactate/pyruvate ratio was below 16; enzymatic activities, when compared to control values, indicated to be independent from the genotype and ranged from 8.5% to 30%, the latter being considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed psychomotor retardation/developmental delay, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially include the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, in silico analysis of the missense mutations present in this PDC deficient population allowed to envisage the molecular mechanism underlying these pathogenic variants. Conclusion: The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allow to obtain an insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.info:eu-repo/semantics/publishedVersio

Congenital Disorders of Glycosylation in Portugal—Two Decades of Experience

Objective: To describe the clinical, biochemical, and genetic features of both new and previously reported patients with congenital disorders of glycosylation (CDGs) diagnosed in Portugal over the last 20 years. Study design: The cohort includes patients with an unexplained multisystem or single organ involvement, with or without psychomotor disability. Serum sialotransferrin isoforms and, whenever necessary, apolipoprotein CIII isoforms and glycan structures were analyzed. Additional studies included measurement of phosphomannomutase (PMM) activity and analysis of lipid-linked oligosaccharides in fibroblasts. Sanger sequencing and massive parallel sequencing were used to identify causal variants or the affected gene, respectively. Results: Sixty-three individuals were diagnosed covering 14 distinct CDGs; 43 patients diagnosed postnatally revealed a type 1, 14 a type 2, and 2 a normal pattern on serum transferrin isoelectrofocusing. The latter patients were identified by whole exome sequencing. Nine of them presented also a hypoglycosylation pattern on apolipoprotein CIII isoelectrofocusing, pointing to an associated O-glycosylation defect. Most of the patients (62%) are PMM2-CDG and the remaining carry pathogenic variants in ALG1, ATP6AP1, ATP6AP2, ATP6V0A2, CCDC115, COG1, COG4, DPAGT1, MAN1B1, SLC35A2, SRD5A3, RFT1, or PGM1. Conclusions: Portuguese patients with CDGs are presented in this report, some of them showing unique clinical phenotypes. Among the 14 genes mutated in Portuguese individuals, 8 are shared with a previously reported Spanish cohort. However, regarding the mutational spectrum of PMM2-CDG, the most frequent CDG, a striking similarity between the 2 populations was found, as only 1 mutated allele found in the Portuguese group has not been reported in Spain.info:eu-repo/semantics/publishedVersio

Diagnosis of pericardial cysts using diffusion weighted magnetic resonance imaging: A case series

<p>Abstract</p> <p>Introduction</p> <p>Congenital pericardial cysts are benign lesions that arise from the pericardium during embryonic development. The diagnosis is based on typical imaging features, but atypical locations and signal magnetic resonance imaging sequences make it difficult to exclude other lesions. Diffusion-weighted magnetic resonance imaging is a novel method that can be used to differentiate tissues based on their restriction to proton diffusion. Its use in differentiating pericardial cysts from other pericardial lesions has not yet been described.</p> <p>Case presentation</p> <p>We present three cases (a 51-year-old Caucasian woman, a 66-year-old Caucasian woman and a 77-year-old Caucasian woman) with pericardial cysts evaluated with diffusion-weighted imaging using cardiac magnetic resonance imaging. Each lesion demonstrated a high apparent diffusion coefficient similar to that of free water.</p> <p>Conclusion</p> <p>This case series is the first attempt to investigate the utility of diffusion-weighted magnetic resonance imaging in the assessment of pericardial cysts. Diffusion-weighted imaging may be a useful noninvasive diagnostic tool for pericardial cysts when conventional imaging findings are inconclusive.</p

Construct validity of a figure rating scale for Brazilian adolescents

<p>Abstract</p> <p>Background</p> <p>Figure rating scales were developed as a tool to determine body dissatisfaction in women, men, and children. However, it lacks in the literature the validation of the scale for body silhouettes previously adapted. We aimed to obtain evidence for construct validity of a figure rating scale for Brazilian adolescents.</p> <p>Methods</p> <p>The study was carried out with adolescent students attending three public schools in an urban region of the municipality of Florianopolis in the State of Santa Catarina (SC). The sample comprised 232 10-19-year-old students, 106 of whom are boys and 126 girls, from the 5th "series" (i.e. year) of Primary School to the 3rd year of Secondary School. Data-gathering involved the application of an instrument containing 8 body figure drawings representing a range of children's and adolescents' body shapes, ranging from very slim (contour 1) to obese (contour 8). Weights and heights were also collected, and body mass index (BMI) was calculated later. BMI was analyzed as a continuous variable, using z-scores, and as a dichotomous categorical variable, representing a diagnosis of nutritional status (normal and overweight including obesity).</p> <p>Results</p> <p>Results showed that both males and females with larger BMI z-scores chose larger body contours. Girls with higher BMI z-scores also show higher values of body image dissatisfaction.</p> <p>Conclusion</p> <p>We provided the first evidence of validity for a figure rating scale for Brazilian adolescents.</p

Oral tolerance inhibits pulmonary eosinophilia in a cockroach allergen induced model of asthma: a randomized laboratory study

<p>Abstract</p> <p>Background</p> <p>Antigen desensitization through oral tolerance is becoming an increasingly attractive treatment option for allergic diseases. However, the mechanism(s) by which tolerization is achieved remain poorly defined. In this study we endeavored to induce oral tolerance to cockroach allergen (CRA: a complex mixture of insect components) in order to ameliorate asthma-like, allergic pulmonary inflammation.</p> <p>Methods</p> <p>We compared the pulmonary inflammation of mice which had received four CRA feedings prior to intratracheal allergen sensitization and challenge to mice fed PBS on the same time course. Respiratory parameters were assessed by whole body unrestrained plethysmography and mechanical ventilation with forced oscillation. Bronchoalveolar lavage fluid (BAL) and lung homogenate (LH) were assessed for cytokines and chemokines by ELISA. BAL inflammatory cells were also collected and examined by light microscopy.</p> <p>Results</p> <p>CRA feeding prior to allergen sensitization and challenge led to a significant improvement in respiratory health. Airways hyperreactivity measured indirectly via enhanced pause (Penh) was meaningfully reduced in the CRA-fed mice compared to the PBS fed mice (2.3 ± 0.4 vs 3.9 ± 0.6; p = 0.03). Directly measured airways resistance confirmed this trend when comparing the CRA-fed to the PBS-fed animals (2.97 ± 0.98 vs 4.95 ± 1.41). This effect was not due to reduced traditional inflammatory cell chemotactic factors, Th2 or other cytokines and chemokines. The mechanism of improved respiratory health in the tolerized mice was due to significantly reduced eosinophil numbers in the bronchoalveolar lavage fluid (43300 ± 11445 vs 158786 ± 38908; p = 0.007) and eosinophil specific peroxidase activity in the lung homogenate (0.59 ± 0.13 vs 1.19 ± 0.19; p = 0.017). The decreased eosinophilia was likely the result of increased IL-10 in the lung homogenate of the tolerized mice (6320 ± 354 ng/mL vs 5190 ± 404 ng/mL, p = 0.02).</p> <p>Conclusion</p> <p>Our results show that oral tolerization to CRA can improve the respiratory health of experimental mice in a CRA-induced model of asthma-like pulmonary inflammation by reducing pulmonary eosinophilia.</p